Pharmaceutical composition for treatment of increased intraocular pressure

ABSTRACT

The invention provides novel pharmaceutical compositions based on semifluorinated alkanes which are useful as carriers for a broad range of active ingredients. Preferred active ingredients include poorly water-soluble prostaglandin analogues. The invention further provides kits comprising such compositions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/017,805, filed on Jun. 25, 2018, which is a division of U.S.application Ser. No. 13/581,396, filed on Aug. 27, 2012, which is aNational Stage Application filed under 35 U.S.C. § 371 of InternationalApplication No. PCT/EP2011/053949 filed on Mar. 16, 2011, which claimsbenefit to and priority of European Patent Application No. 10002800.0filed on Mar. 17, 2010, the contents of each of which are herebyincorporated by reference in their entireties.

BACKGROUND

Increased intraocular pressure is a frequent disorder of the eye whichis often associated with optic nerve damage, in which case the diseaseis glaucoma. In the absence of optic nerve damage, the condition isreferred to as ocular hypertension.

Normal intraocular pressure is usually defined as being in the rangefrom 10 to 21 mmHg. The pressure results predominantly from balancebetween the production rate and the drainage rate of the aqueous humourin the eye. In addition, it is influenced by the corneal thickness andrigidity. The intraocular pressure typically fluctuates around about 15to 16 mmHg with amplitudes of up to 6 mmHg. For example, it usuallydecreases in the night due to a decreased production of aqueous humour.It also responds to various physiological factors such as exercise,heart rate, respiration, fluid intake, as well as certain types ofsystemic or topical drugs.

The aqueous humour is produced by the ciliary bodies of the eye, fromwhere it flows into the posterior chamber. The composition of theaqueous humour is very similar to that of blood plasma but differs fromthe latter by a lower protein content. Its main constituents are water(99%), electrolytes (inorganic ions to maintain the physiological pH),low amounts of albumin and β-globulins, ascorbate, glucose, lactate, andamino acids.

From the posterior chamber, the aqueous humour is distributed via thepupil of the iris into the anterior chamber of the eye. From here, itflows through the so-called trabecular meshwork, which is a spongytissue area lined by trabeculocytes whose main function is to drain thehumour into a set of tubes called Schlemm's canal, from where the humourenters the blood circulation. The humour flow from the trabecularmeshwork into the Schlemm's canal occurs via two different routes:either directly via the aqueous vein to the episcleral vein, orindirectly via collector channels to the episcleral vein by intrascleralplexus. This trabecular outflow pathway accounts for the major fractionof drained aqueous humour. In addition, there exists a second majordrainage pathway which is the uveoscleral outflow, which is relativelyindependent of the intraocular pressure and normally accounts for only 5to 10% of the aqueous humour drainage in healthy humans.

Both in the trabecular meshwork and in the uveoscleral tissue, variousprostanoid receptors have been found, which indicates that prostanoidsare involved in the regulation of aqueous humour production and/ordrainage and thereby influence the intraocular pressure. In thetrabecular network, genes encoding the EP, FP, IP, DP and TP receptorfamilies are expressed, whereas the EP and FP receptor families aredominant in the uveoscleral tissue (Toris et al., Surv Ophthalmol. 2008;53, Suppl. 1, S107-S120).

Prostanoids are physiological fatty acid derivatives representing asubclass of eicosanoids. They comprise prostaglandins, prostamides,thromboxanes, and prostacyclins, all of which compounds are mediatorsinvolved in numerous physiological processes. Natural prostaglandinssuch as PGF₂, PGE₂, PGD₂, and PGI₂ exhibit a particular affinity totheir respective receptors (FP, EP, DP, IP), but also have somenon-selective affinity for other prostaglandin receptors (ibid.).Prostaglandins also have direct effects on matrix metalloproteinases.These are neutral proteinases expressed in the trabecular meshwork whichplay a role in controlling humour outflow resistance by degrading theextracellular matrix.

Several prostaglandin analogues have been found effective as topicallyadministered medicines in reducing the intraocular pressure, such aslatanoprost, bimatoprost, tafluprost, travoprost and unoprostone. Bysome experts, bimatoprost is understood as a prostamide rather thanprostaglandin derivative.

Latanoprost, travoprost, tafluprost and probably also bimatoprost arepotent and selective PGF₂ agonists. Their net effect is a reduction ofintraocular pressure, which is predominantly caused by a substantialincrease in aqueous humour drainage via the uveoscleral pathway.Probably they also increase the trabecular outflow to some degree.

Unoprostone is sometimes also classified as a PGF₂ analogue even thoughits potency and selectivity are much lower than in the case of thepreviously mentioned compounds. It is most closely related to apulmonary metabolite of PGF₂. It is also capable of reducing theintraocular pressure, but appears to act predominantly by stimulatingthe trabecular drainage pathway, whereas it has little effect on theuveoscleral outflow.

Various eye drop formulations comprising prostaglandin analogues havebeen developed and are commercially available. Latanoprost andtravoprost are provided as buffered, isotonised, preserved aqueoussolutions in multidose bottles having a strength of 50 μg/mL (0.005%)and 40 μg/mL (0.004%), respectively. Tafluprost is available in asimilar preserved formulations as well as in a non-preserved formulationin single-dose containers. The tafluprost formulations have a strengthof 15 μg/mL (0.0015%) and additionally contain the surfactant,polysorbate 80. Bimatoprost is also marketed as a buffered, isotonised,and preserved aqueous solution; its strength is 0.3 mg/mL (0.03%). Thestrength of the commercial unoprostone formulation is 1.5 mg/mL (0.15%).It contains buffer, a preservative, an isotonising agent, andpolysorbate 80.

However, preserved aqueous formulations for ophthalmic use aredisadvantageous in that they are capable of producing irritancies orhypersensitivity reaction, in particular in long-term use, such as inglaucoma therapy. The most common preservative in the formulationsmentioned above is benzalkonium chloride, a quaternary ammonium compoundwhich is associated with frequent irritant toxic reactions.Non-preserved single use containers avoid this disadvantage, but theyare expensive. Not only do they require a container for each singledose, but also an overfill of the formulation, which means that asubstantial fraction (if not most) of the actual medicine remains in thecontainer and is discharged as waste. Considering the drug in an eyedrop which is actually administered into the eye, only a fraction ofthat becomes effective due to the limited volume capacity of thelacrimal sac: a significant fraction of the administered fluid volume isexpelled by the blinking of the eyelids, and another fraction is takenup systemically via the nasolacrimal duct, which potentially leads toadverse drug effects.

In spite of the preservative contained in the currently availableformulation of latanoprost, there have been reports of bacterialkeratitis caused by microbiological contamination of the productassumingly by the patients themselves, indicating that themicrobiological safety of the product is only relative.

An alternative to aqueous eye drop formulations are oil-based ophthalmiccompositions. They are often capable of better dissolving poorlywater-soluble drug substances. Moreover, they do not normally requirethe incorporation of pH adjusting agents or isotonising agents.

One of the disadvantages of all oil-based formulations for ophthalmicadministration is that inherently have a negative impact on vision.Whether used as oily solutions or oil-in-water emulsions, they exhibit arefractive index which differs substantially from that of physiologicaltear fluid, which leads to visual disturbances and blurring.

Moreover, oil-based formulations do not readily mix with tear fluid toform a homogenous liquid phase. Oily solutions are altogether immisciblewith the aqueous tear fluid, and the exact fate of an emulsion mixedwith tear fluid in a physiological setting is not completelypredictable.

Oil-in-water emulsions of poorly water-soluble drugs like ciclosporinfurther exhibit the disadvantage that they have a limited drug loadcapacity. While the active ingredient may have some solubility in theoil phase, this phase is only dispersed in the coherent aqueous phase ofthe emulsion so that the maximum overall drug concentration in theformulation is very limited.

In contrast to single phase systems such as aqueous or oily solutions,oil-in-water emulsions are also more complex and difficult tomanufacture, especially in sterile form. Frequently, emulsions are notreadily sterilisable by thermal treatment without negative impact on thephysical properties of the emulsion. On the other hand, asepticprocessing is complex, costly, and is associated with higher risks offailure, i.e. microbial contamination of the product.

Furthermore, oil-in-water emulsions are like aqueous solutions prone tomicrobial contamination during use. If they were to be presented inmulti-dose containers which are in principle more cost-efficient andconvenient for patients than single-use vials, they would have to bepreserved in order to ensure their microbiological quality. At the sametime, preservatives which can be used in ophthalmic formulations arepotentially irritating, as mentioned above, or even damaging to the eye.

WO 2005/123035 discloses hydrophobic compositions which may be useful asophthalmic drug formulations. The compositions may be used to treatvarious ophthalmic diseases and conditions including glaucoma and maycomprise a therapeutic agent selected from various different therapeuticcategories such as antibiotics, antimicrobials, antifungal agents,antiviral agents, antiparasitic agents, antiallergic agents,anti-inflammatory agents, alkylating agents, prostaglandin analogues andbeta-blockers, cholinergic agents, vasoconstrictors, pupil sizemanagement agents, glaucoma agents, macular degeneration agents, andagents to arrest the development of cataracts. The hydrophobicity of thecomposition is achieved by selecting a hydrophobic liquid vehicle,selected in particular from silicon polymers, fluorinated siliconpolymers, perfluorocarbons, fluorinated alcohols, and perfluorinatedpolyethers, and mixtures thereof. However, the only specific compositiondisclosed in the document does not incorporate an active ingredient, butis merely a vehicle consisting of a mixture of two silicon polymers,namely dimethicone and cyclomethicone, which have been combined so as toyield a viscosity of about 8,000 centistokes.

US 2002/128527 discloses semifluorinated alkanes and their preparation,and proposes their use as vehicles in ophthalmic preparations. However,it does not disclose any specific compositions comprising asemifluorinated alkane and an incorporated active ingredient. Neitherdoes it mention the treatment of glaucoma or the incorporation of aprostaglandin analogue. It is also silent about ophthalmic vehiclescomprising mixtures of semifluorinated alkanes and cosolvents.

U.S. Pat. No. 7,026,359 describes the use of highly fluorinatedoligomeric alkanes in ophthalmology. These highly fluorinated compounds,whose chemical structure is different from that of the semifluorinatedalkanes referred to in US 2002/128527, represent a large group ofhydrocarbons having 2 to 6 perfluorinated side chains. The document doesnot mention any specific composition comprising such a fluorinatedcompound and an active ingredient. In fact, it does not make anyreference to any particular active agent at all, or even to any specificchemically or functionally defined class of active ingredients. Neitherdoes it disclose any specific therapeutic indications withinophthalmology in which the use of the highly fluorinated compounds couldbe useful.

U.S. Pat. No. 5,874,481 is directed to thermodynamically stablemolecular solutions of lipophilic active ingredients in mixtures of alipophilic fluorochemical and a non-fluorinated cosolvent. While thepatent in a very general manner refers to numerous classes oftherapeutic compounds from which the active ingredient may be selected,including ophthalmic agents, it only provides very few specificcomposition comprising a selected active ingredient, namely solutions ofdiazepam, caffeine and prednisone, respectively, all of which aresystemic rather than ophthalmic therapeutic agents.

It is an object of the present invention to provide a novelpharmaceutical composition which is useful in the treatment of increasedintraocular pressure, e.g. in association with open-angle glaucoma orocular hypertension, which these issues discussed above and overcomes atleast one of the limitations or disadvantages associated with prior artformulations. In a specific aspect, it is an object of the invention toprovide an ophthalmic composition which has the capacity to incorporatesubstantial amounts of poorly water-soluble drug substances useful inthe management of open-angle glaucoma and/or ocular hypertension. In afurther aspect, it is an object of the invention to provide apharmaceutical kit comprising a composition for the treatment ofincreased intraocular pressure which does not exhibit one or more of thedisadvantages of prior art. Further objects of the invention will becomeclear on the basis of the following description, examples, and patentclaims.

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical composition comprising apoorly water-soluble prostaglandin analogue useful in the management ofincreased intraocular pressure or a symptom associated therewith. Thecomposition further comprises a liquid vehicle comprising asemifluorinated alkane.

In one of the preferred embodiments, the composition comprises atherapeutically effective amount of a poorly water-soluble prostaglandinanalogue selected from the group consisting of latanoprost, bimatoprost,tafluprost, travoprost and unoprostone. It is furthermore preferred thatthe composition is in liquid form and adapted to be administeredtopically to the eye of a patient.

In a further aspect, the invention provides the use of such compositionin the prevention or therapy of increased intraocular pressure, ocularhypertension, glaucoma, or any symptom associated therewith, wherein theprevention or treatment is preferably performed by administering thecomposition into the eye of a patient.

In yet a further aspect, the invention provides a pharmaceutical kitcomprising such composition in a container which has a dispensing meansadapted for topically administering the composition to the eye of apatient.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the invention provides a pharmaceutical compositioncomprising a therapeutically effective amount of a poorly water-solubleprostaglandin analogue useful in the prevention or therapy of increasedintraocular pressure or a symptom associated therewith. The compositionis further characterised in that it comprises a liquid vehiclecomprising a semifluorinated alkane.

As used herein, a pharmaceutical composition is a composition comprisingat least one pharmacologically active ingredient or diagnostic agent incombination with at least one pharmaceutical excipient. Atherapeutically effective amount refers to a dose, concentration orstrength which is useful for producing a desired pharmacological effect.

As described above, increased intraocular pressure may be associatedwith optic nerve damage, in which case the disease is glaucoma. In theabsence of optic nerve damage, the condition is referred to as ocularhypertension. Increased intraocular pressure may be associated with avariety of conditions such as orbital oedema, traumatic hyphema,pupillary block, postoperative viscoelastic retention, intraocularinflammation, or corticosteroid use. Increased intraocular pressure isalso a major risk factor for the development of glaucoma. Vice versa,glaucoma itself very often involves increased intraocular pressure.Further symptoms which may be directly or indirectly associated withincreased intraocular pressure or with glaucoma in combination withincreased intraocular pressure include optic neuropathy, dischaemorrhage, nerve fiber layer defects, notching, vertical ovalisationof the cup, asymmetric and/or progressive cupping, loss of visual field,halos, blurred vision, eye pain etc.

The active ingredient is selected from the group of poorly water-solubleprostaglandin analogues. Examples of such prostaglandin analoguesinclude latanoprost, bimatoprost, tafluprost, travoprost andunoprostone. A particularly preferred active ingredient is latanoprost.

Some of the key advantages of the present invention are brought about bythe presence of a semifluorinated alkane in the composition.Semifluorinated alkanes are linear or branched alkanes some of whosehydrogen atoms have been replaced by fluorine. In a preferredembodiment, the semifluorinated alkanes (SFA's) used in the presentinvention are composed of at least one non-fluorinated hydrocarbonsegment and at least one perfluorinated hydrocarbon segment.Particularly useful are SFA's which have one non-fluorinated hydrocarbonsegment attached to one perfluorinated hydrocarbon segment, according tothe general formula F(CF₂)_(n)(CH₂)_(m)H, or two perfluorinatedhydrocarbon segments separated by one non-fluorinated hydrocarbonsegment, according to the general formula F(CF₂)_(n)(CH₂)_(m)(CF₂)_(o)F.

Another nomenclature which is used herein refers to the above-mentionedSFA's having two or three segments as RFRH and RFRHRF, respectively,wherein R_(F) designates a perfluorated hydrocarbon segment, R_(H)designates a non-fluorinated segment. Alternatively, the compounds maybe referred to as FnHm and FnHmFo, respectively, wherein F means aperfluorated hydrocarbon segment, H means a non-fluorinated segment, andn, m and o is the number of carbon atoms of the respective segment. Forexample, F3H3 is used for perfluoropropylpropane. Moreover, this type ofnomenclature is usually used for compounds having linear segments.Therefore, unless otherwise indicated, it should be assumed that F3H3means 1-perfluoropropylpropane, rather than 2-perfluoropropylpropane,1-perfluoroisopropylpropane or 2-perfluoroisopropylpropane.

Preferably, the semifluorinated alkanes according to the generalformulas F(CF₂)_(n)(CH₂)_(m)H and F(CF₂)_(n)(CH₂)_(m)(CF₂)_(o)F havesegment sizes ranging from 3 to 20 carbon atoms, i.e. n, m and o areindependently selected in the range from 3 to 20. SFA's which are usefulin the context of the present invention are also described in EP-A 965334, EP-A 965329 and EP-A 2110126, the disclosure of which documents isincorporated herein.

In a further embodiment, the semifluorinated alkane is a compoundaccording to the formula RFRH, whose segments R_(F) and R_(H) are linearand each—but independently from one another—have from 3 to 20 carbonatoms. In another particular embodiment, the perfluorinated segment islinear and comprises from 4 to 12 carbon atoms, and/or thenon-fluorinated segment is linear and comprises from 4 to 8 carbonatoms. Preferred SFA's include in particular the compounds F4H5, F4H6,F6H4, F6H6, F6H8, and F6H10. Presently most preferred for carrying outthe invention are F4H5, F4H6, F6H6 and F6H8.

Optionally, the composition may comprise more than one SFA. It may beuseful to combine SFA's, for example, in order to achieve a particulartarget property such as a certain density or viscosity. If a mixture ofSFA's is used, it is furthermore preferred that the mixture comprises atleast one of F4H5, F4H6, F6H4, F6H6, F6H8, and F6H10, and in particularone of F4H5, F6H6 and F6H8. In another embodiment, the mixture comprisesat least two members selected from F4H5, F4H6, F6H4, F6H6, F6H8, andF6H10, and in particular at least two members selected from F4H5, F6H6and F6H8.

Liquid SFA's are chemically and physiologically inert, colourless andstable. Their typical densities range from 1.1 to 1.7 g/cm³, and theirsurface tension may be as low as 19 mN/m. SFA's of the RFRH type areinsoluble in water but also somewhat amphiphilic, with increasinglipophilicity correlating with an increasing size of the non-fluorinatedsegment.

Liquid SFA's of the RFRH type are being used commercially for unfoldingand reapplying a retina, for long-term tamponade as vitreous humoursubstitute (H. Meinert et al., European Journal of Ophthalmology, Vol.10(3), pp. 189-197, 2000), and as wash-out solutions for residualsilicon oil after vitreo-retinal surgery. Experimentally, they have alsobeen used as blood substitutes (H. Meinert et al., Biomaterials,Artificial Cells, and Immobilization Biotechnology, Vol. 21(5), pp.583-95, 1993). These applications have established SFA's asphysiologically well tolerated compounds.

On the other hand, SFA's have not been used as excipients in approveddrug products as of today.

It has now surprisingly been found by the inventors that SFA's areparticularly suitable as carriers, vehicles or excipients in ophthalmiccompositions for topical administration. This is based on the fact thatSFA's are capable of dissolving many poorly water-soluble compoundswhich are of interest in ophthalmology, but also on the discovery thatthey are unexpectedly well-tolerated by the eye, as shown in preclinicaltesting. This is very surprising as organic or non-aqueous solvents,perhaps with the exception of oily compounds, are typically veryirritating or even highly damaging when administered topically to aneye.

Compared to oily carriers or vehicles in ophthalmic compositions fortopical use, SFA's exhibit a refractive index which is much bettercompatible with the aim of a minimally affected vision: While oilypreparation lead to a blurry vision and can therefore not beadministered in any situation in which the patient needs a clear vision,SFA's cause little or no blurring.

By illustration, the refractive index of tear fluid is close to that ofwater, i.e. 1.333 at room temperature (RT). Oils typically have asubstantially higher refractive index such as about 1.46 (peanut oil),1.47 (sesame oil), or 1.48 (castor oil). In contrast, the inventors havedetermined the refractive indices of various SFA's of interest to be inthe region of 1.29 to 1.35, i.e. much closer to that of water. In one ofthe specific embodiments, the invention is therefore practised with anSFA whose refractive index is from 1.29 to 1.35, and in particular fromabout 1.30 to about 1.35 at 20° C. The refractive index for selectedSFA's is shown in table 1.

Moreover, SFA's exhibit a remarkable wetting and spreading behaviour bywhich they deliver an incorporated active ingredient rapidly andeffectively to the corneal surface and conjunctiva. Wetting means theability of a liquid to establish and maintain contact with a solidsurface, resulting from intermolecular interactions when the two arebrought together. The balance between adhesive and cohesive forcesdetermines the degree of wetting. The higher the adhesive forcescompared to the cohesive forces, the more a drop of liquid will spreadacross the surface of the solid material. Conversely, very high cohesiveforces within the liquid will cause the drop to form a sphere, thusavoiding contact with the surface. Similarly, spreading may also occurat the interface of two liquids which are brought into contact with eachother.

TABLE 1 SFA Refractive index F4H4 1.308 F4H5 1.3204 F4H6 1.334 F4H71.3357 F4H8 1.348 F6H2 1.295 F6H4 1.306 F6H6 1.3224 F6H7 1.3366 F6H81.3432 F6H9 1.3494

A measure for wetting and spreading is the contact angle θ. The contactangle is the angle at which the liquid-vapour interface meets thesolid-liquid or liquid-liquid interface. The tendency of a drop tospread out increases as the contact angle decreases. Thus, the contactangle provides an inverse measure of wettability.

A low contact angle of less than 90° indicates high wettability and/orspreading, whereas a higher contact angle indicates poor wettability andspreading. Perfect wetting and spreading results in a contact angle of0°, also reported as no measurable contact angle.

The inventors have found that the SFA's used in the present invention,in particular the preferred SFA's, exhibit an excellent wetting ofvarious surfaces which are not easily wetted by conventional drugformulations. For example, the contact angle of both F4H5 and F6H8 ontablets compressed from either trospium chloride or fenofibrate (150 mgof drug substance compressed at 15-20 kN to tablets of 13 mm indiameter) was not measurable, i.e. perfect wetting occurred. It is notedthat fenofibrate is an example of a hydrophobic, poorly water-solublecompound, whereas trospium chloride is hydrophilic and water-soluble. Incomparison, the contact angle of purified water on the fenofibratetablet was determined as 92.5°, i.e. the tablet was poorly wetted bywater.

A further surprising advantage of SFA's found by the inventors is thatthey appear to form very small droplets when dispensed from a droppersuch as an eye dropper. Without wishing to be bound by theory, it isbelieved that the small droplet size is a result of an interplay of theSFA's unique properties in terms of their density, viscosity, andsurface tension. In any case, it is believed that for topicaladministration into an eye a small drop or volume of administration ishighly advantageous as the capability of the lacrimal sac to accept andhold fluid is extremely limited. In fact, it is very common that theadministration of a conventional eye drop formulation based on water oroil immediately leads to a discharge of a substantial fraction of theadministered medicine as well as some tear fluid. At the same time,there is a risk that some of the administered dose will be taken upsystemically via the nasolacrimal duct. Hence, if an effective dose ofan active ingredient can be incorporated in a small volume of liquidwhich can be dispensed as a very small droplet, this should lead to asubstantially increased dosing reliability and reproducibility, thusenhancing the safety and effectiveness of the therapy.

A yet further advantage of the invention which is based on the use ofSFA's is that they can be designed or mixed for an optimally adjustedevaporation behaviour after administration. Thus it is possible toformulate an ophthalmic composition which delivers an active compoundefficiently to the eye in such a way that the liquid vehicles issubsequently eliminated via evaporation. This is in sharp contrast tooily eye drop vehicles which do not evaporate and thus formnon-physiological residues at the site of administration, e.g. in thelacrimal sac.

Moreover, the invention provides a means of formulating non-aqueousophthalmic compositions which are microbiologically stable. This is dueto the fact that SFA's are not normally prone to microbialcontamination. Hence, it is possible to formulate preservative-freeophthalmic compositions which are better tolerable for many patients, inparticular patients suffering from ophthalmic disorders.

As mentioned, the active ingredient to be selected for carrying out theinvention is a compound useful in the management, prevention or therapyof increased intraocular pressure, or of any symptom associated withthis condition, and selected from the group of poorly water-solubleprostaglandin analogues.

It is believed that the invention is particularly useful if the activecompound is selected from poorly water-soluble drug substances which areotherwise challenging to formulate for ophthalmic use. As used herein, acompound is poorly water-soluble if it exhibits a solubility fallinginto the definitions of “sparingly soluble”, “slightly soluble”, “veryslightly soluble”, or “practically insoluble” (according to Ph. Eur. 6thEd.). Particularly preferred are active ingredients which are “veryslightly soluble” or “practically insoluble”. In another embodiment, itis preferred that the active ingredient exhibits a water solubility ofless than about 1 mg per mL, as measured at room temperature (between 15and 25° C.) and at neutral pH (pH 6.0 and pH 8.0).

Examples of preferred active compounds include latanoprost, bimatoprost,tafluprost, travoprost and unoprostone. Latanoprost, also known asisopropyl-(Z)-7 [(1R,2R,3R,5S)3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate,like travoprost and unoprostone, is a colourless to slightly yellow oiland practically insoluble in water. The IUPAC name of travoprost ispropan-2-yl 7-[3,5-dihydroxy-2-[3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-but-1-enyl]-cyclopentyl]hept-5-enoate. Unoprostone is currentlyused as unoprostone isopropyl, also known as isopropyl (+)-(Z)-7-[(1R,2R, 3R, 5S)-3,5-dihydroxy-2-(3-oxodecyl)cyclopentyl]-5-heptenoate.Bimatoprost may also be referred to as7-[3,5-dihydroxy-2-(3-hydroxy-5-phenyl-pent-1-enyl)-cyclopentyl]-N-ethyl-hept-5-enamide.Bimatoprost, or(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-[(1E,3S)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-N-ethyl-5-heptenamide,is a powder and slightly soluble in water. The chemical name oftafluprost is isopropyl(5Z)-7-{(1R,2R,3R,5S)-2-[(1E)-3,3-difluoro-4-phenoxybut-1-en-1-yl]-3,5-dihydroxycyclopentyl}hept-5-enoate.

A particularly preferred active compound according to the presentinvention is latanoprost. Latanoprost may be incorporated in acomposition of the invention at any therapeutically usefulconcentration, such as from about 1 μg/ml to about 1 mg/ml. In furtherembodiments, the concentration of latanoprost is from about 10 μg/ml toabout 500 μg/ml, or at least about 20 μg/ml, or from about 20 μg/ml toabout 100 μg/ml. In the case of other active ingredients, the preferredconcentrations may be different. For example, unoprostone or unoprostoneisopropyl may be incorporated at a concentration of about 0.1 mg/ml toabout 10 mg/ml, or from about 0.5 mg/ml to about 5 mg/ml, respectively.

It is also preferred that the active ingredient is incorporated in thedissolved state. This allows the composition to be formulated as a clearsolution. Alternatively, the composition may also be designed as asuspension or emulsion.

It has been found by the inventors that certain SFA's have asurprisingly high capacity to dissolve even extremely challenging poorlysoluble compounds. In some of the preferred embodiments, ophthalmicsolutions comprise an SFA selected from F4H5, F4H6, F6H6, and F6H8 andlatanoprost as active ingredient. Within these embodiments, it ispreferred that the concentration of latanoprost is about 0.001 wt.-% toabout 0.01 wt.-%.

Depending on the active ingredient, its dose and the SFA or mixture ofSFA's selected as carrier, it may be useful to add another liquidexcipient in order to ensure that the active compound can beincorporated in completely dissolved form. Such other liquid excipientis preferably an organic cosolvent, such as an oil selected fromglyceride oils, liquid waxes, and liquid paraffin, or an organic solventexhibiting a high degree of biocompatibility.

Examples of potentially useful oily excipients which may be used incombination with one or more SFA's include triglyceride oils (i.e.soybean oil, olive oil, sesame oil, cotton seed oil, castor oil, sweetalmond oil), mineral oil (i.e. petrolatum and liquid paraffin), mediumchain triglycerides (MCT), oily fatty acids, isopropyl myristate, oilyfatty alcohols, esters of sorbitol and fatty acids, oily sucrose esters,or any other oily substance which is physiologically tolerated by theeye. In one of the preferred embodiments, the concentration of the oilyexcipient is up to about 30 wt.-%, such as in the range from about 0.1to 20 wt.-%.

Examples of potentially useful organic solvents include glycerol,propylene glycol, polyethylene glycol, and ethanol. However, theconcentration of the cosolvent should preferably be low relative to thatof the SFA or SFA mixture. If an organic solvent such as ethanol isused, it is recommendable to keep it below a level of approx 5 wt.-%.More preferably, the content of ethanol is from about 0.1 to about 2wt.-%, and most preferably not more than about 1.5 wt.-%.

While ethanol, generally speaking, is not very well tolerated by thehuman eye, it has surprisingly been found by the inventors that mixturesof semifluorinated alkanes with very small amounts of ethanol, such as 1wt.-%, are capable of dissolving substantially higher amounts of ahydrophobic, poorly soluble compound such as latanoprost, whereas thetolerability of the composition is not negatively affected by theethanol content.

The composition may of course comprise further pharmaceutical excipientsas required or useful. Potentially useful excipients includesurfactants, in particular non-ionic surfactants or amphiphilic lipids,acids, bases, antioxidants, stabilisers, synergists, and—if required ina particular case—a preservative.

Surfactants which are considered potentially useful include tyloxapol,poloxamers such as Pluronic F68LF or Lutrol F68, Pluronic L-G2LF andPluronic L62D, polysorbates such as polysorbate 20 and polysorbate 80,polyoxyethylene castor oil derivatives, sorbitan esters, polyoxylstearates, and mixtures of two or more thereof.

Furthermore, the invention provides a pharmaceutical kit comprising thecomposition as described above and a container holding the composition.Preferably, the container which contains the composition has adispensing means such as a dropping device adapted for topicallyadministering the composition to the eye of a patient.

The following examples serve to illustrate the invention; however, theseare not to be understood as restricting the scope of the invention.

EXAMPLES Example 1

The droplet size of selected SFA's in terms of weight and volume ofdroplets from three droppers was determined and compared to that ofpurified water. The devices used for dispensing the droplets were (a) a2 mL Pasteur pipette (wall thickness 0.53 mm; external tip diameter:1.50 mm; length: 150 mm) made of glass, (b) a 20 G (0.9 mm×50 mm)injection needle, and (c) a dropper from a commercial eye drops product(Hylo-Vision). The droplet weights were measured at 25° C. using alaboratory balance; the volumes were calculated. Each test was performed10 times. The results of the experiments (mean values of droplet sizesand standard deviations) are shown in table 2.

TABLE 2 Glass pipette Injection needle Eye dropper Material mg μL mg μLmg μL Water 31.2 ± 1.4  31.3 ± 1.4  11.0 ± 0.9  11.1 ± 0.9  36.0 ± 2.236.1 ± 2.2 F4H5 6.0 ± 0.4 4.7 ± 0.3 2.6 ± 0.4 2.0 ± 0.3 12.4 ± 0.2  9.6± 0.2 F6H8 6.6 ± 0.6 5.0 ± 0.4 3.4 ± 0.2 2.5 ± 0.1 13.7 ± 0.4 10.3 ± 0.3

Table 2 shows that droplets of F4H5 and F6H8 are dramatically smallerand lighter than water droplets dispensed from the same device. Takinginto account the fact that SFA's have a high capacity to dissolve manyactive ingredients very well, it is concluded that SFA's are highlysuitable liquid vehicles for eye drops which are better retained by thelacrimal sac, produce little spill-over, and thus have a potential todeliver a dose more reliably and reproducibly to the eye thanconventional eye drop formulations.

Example 2

Ethanol was mixed with F4H5 to yield a solution having an ethanolconcentration of 1 wt.-%. The solution was filtered aseptically andfilled into sterile vials. The physiological tolerability of thissolution was evaluated in an ex-vivo eye irritation test (EVEIT) usingrabbit eyes taken from freshly sacrificed animals. The eyes werefastened in chambers coupled micropump systems which continuouslysupplied the eyes with cultivation medium (Minimal Essential Medium, MEMT031-05) without fetal calf serum. The vitality of the eyes wasmonitored by regularly measuring the concentration of lactate andglucose in the chamber eluate. The corneal surface of the eyes wasdamaged by abrasion, using a dental ceramic abrasive (638XF, Meisinger).For each eye, four lesions of 3.0 to 4.5 mm² were prepared.

To evaluate the effect of F4H5 and F4H5 with 1 wt.-% ethanol on thecornea, an amount of approx. 0.25 to 0.50 μl of the respective testsubstance was dropped onto the centre of a cornea once every hour over aperiod of 12 hours, followed by a 12 hour resting period in which thecornea was submersed in culture medium to simulate a closed lid during anight phase. In addition, an aqueous solution of hyaluronic acid (0.1wt.-%) was used as reference (hyaluronic acid is know to enhance therestoration of the corneal surface after damage), culture medium wasused as control, and aqueous benzalkonium chloride solution (0.01 wt.-%)was used as negative control. Each test was performed over a period of 3days. The effects were observed by optical coherence tomography (OCT),by digitally determining the dimensions of the lesions after stainingwith fluorescein, and finally by a histological evaluation of thecorneal epithelium and endothelium at the end of each experiment.

In result, it was found that in particular F4H5 was better toleratedthan culture medium, and that it exhibits a positive effect on thehealing of damaged cornea similar to that of hyaluronic acid. Even whencomprising 1 wt.-% of ethanol, F4H5 is tolerated very well by the eye.OCT imaging revealed no indication of penetration of F4H5 into thecornea.

In more detail, it was found that the lesions prepared by abrasionbecame smaller or larger over time depending on the liquid that wasadministered to the cornea. Substantial healing occurred when F4H5, F4H5with 1 wt.-% ethanol, or hyaluronic acid was used. In marked contrast,benzalkonium chloride administration lead to a rapid growth of thelesions eventually leading to a complete disintegration of the cornealepithelium. Culture medium had an intermediate effect. Tables 3 and 4shows the dimensions of the lesions [mm²] before and after the testswith the various test liquids and controls, respectively.

Morphological and histological evaluation revealed that the corneastreated with F4H5 or hyaluronic acid had not only healed very well, butwere also entirely clear at the end of the tests, with healthy andsmooth surface morphology. Eyes treated with F4H5 with 1 wt.-% ethanolshowed a healthy overall morphology, the corneas were clear and theepithelia revealed only very minor signs of damage remaining from thelesions. In contrast, some of the controls treated with culture mediumshowed significant surface roughness, and the eye treated withbenzalkonium chloride showed not only the complete disintegration of thecorneal epithelium, but also a major impairment of the complete corneaeven including the endothelium.

TABLE 3 F4H5 F4H5 + 1% EtOH Run 1 Run 2 Run 3 Run 1 Run 2 Initial size[mm²] 9.95 12.88 12.09 14.68 14.99 Final size [mm²] 0.19 1.01 0.06 0.302.26 Change [%] −98.1 −99.0 −99.5 −98.0 −84.9 *EtOH: ethanol

TABLE 4 HA MEM Run 1 Run 2 Run 3 Run 1 Run 2 Run 3 BAC Initial size[mm²] 13.22 16.03 14.87 15.5 15.57 13.11 16.05 Final size [mm²] 0.360.24 0.00 2.51 6.83 0.00 >60 Change [%] −97.3 −98.5 −100 −83.8 −56.1−100 ** *HA: hyaluronic acid; BAC: benzalkonium chloride; MEM: minimalessential medium **Lesion essentially covered the complete cornealsurface

Example 3

The ex-vivo eye irritation test (EVEIT) according to example 2 wasrepeated, this time using F6H8 and F6H8 mixed with 1 wt.-% ethanol asvehicles whose tolerability was to be evaluated. Each of the twovehicles was tested in two separate runs. In result, all lesions healedfully during the experimental time (see table 5). Histology showed densestromata with very few clefts and well-arranged keratocytes.

TABLE 5 F6H8 F6H8 + 1% EtOH Run 1 Run 2 Run 1 Run 2 Initial size [mm²]10.54 12.08 16.65 11.29 Final size [mm²] 0.00 0.00 0.00 0.00 Change [%]−100.0 −100.0 −100.0 −100.0

Example 4

0.25 mg of latanoprost were dissolved in 5 ml of a solution of ethanol(1 wt.-%) in F4H5. The resulting clear solution having a latanoprostconcentration of 0.05 mg/ml (0.005% w/v) was aseptically filtered andfilled into sterile vials. The refractive index at 20° C. was 1.322.

In a separate experiment, the solubility of latanoprost in a mixture ofF4H5 and ethanol (ratio 99:1 by weight) was determined by HPLC accordingto Ph. Eur. 2.2.29 after rotation evaporation of the solvent methylacetate in vacuo, addition of the solvent under examination of theresidue and determination of the dissolved amount. The solubility wasfound to be 0.057 mg/mL.

Example 5

1.5 mg of bimatoprost were dissolved in 5 ml of a solution of ethanol (1wt.-%) in a mixture of F4H5 and F6H8 (1:1). The resulting clear solutionhaving a bimatoprost concentration of 0.3 mg/ml (0.03% w/v) wasaseptically filtered and filled into sterile vials. The refractive indexat 20° C. was 1.333.

Example 6

0.075 mg of tafluprost and 20 mg of alpha-tocopherol were dissolved in 5ml of a solution of ethanol (1 wt.-%) and medium-chain triglycerides (10wt.-%) in F6H8. The resulting clear solution having a tafluprostconcentration of 0.015 mg/ml (0.0015% w/v) and an alpha-tocopherolconcentration of 4 mg/ml was aseptically filtered and filled intosterile vials. The refractive index at 20° C. was 1.359.

Example 7

0.2 mg of travoprost were dissolved in 5 ml of a solution of ethanol (1wt.-%) in F6H6. The resulting clear solution having travoprost aconcentration of 0.04 mg/ml (0.004% w/v) was aseptically filtered andfilled into sterile vials. The refractive index at 20° C. was 1.331.

Example 8

7.5 mg of unoprostone were dissolved in 5 ml of a solution of ethanol (1wt.-%) in F4H6. The resulting clear solution having a unoprostoneconcentration of 1.5 mg/ml (0.15% w/v) was aseptically filtered andfilled into sterile vials. The refractive index at 20° C. was 1.334.

Example 9

0.5 mg of latanoprost were dissolved in 5 ml of a solution of ethanol(0.75 wt.-%) in a mixture of F4H5 and F4H6 (1:2). The resulting clearsolution having a latanoprost concentration of 0.1 mg/ml (0.01% w/v) wasaseptically filtered and filled into sterile vials. The refractive indexat 20° C. was 1.336.

Example 10

0.25 mg of latanoprost were dissolved in 5 ml of a solution of ethanol(0.5 wt.-%) and olive oil (4 mg/ml) in F4H5. The resulting clearsolution having a latanoprost concentration of 0.05 mg/ml (0.005% w/v)was aseptically filtered and filled into sterile vials. The refractiveindex at 20° C. was 1.322.

Example 11

0.25 mg of latanoprost were dissolved in 5 ml of a solution of ethanol(0.25 wt.-%) in F4H6. The resulting clear solution having a latanoprostconcentration of 0.05 mg/ml (0.005% w/v) was aseptically filtered andfilled into sterile vials. The refractive index at 20° C. was 1.334.

Example 12

An antimicrobial preservative effectiveness test in analogy to that ofUSP 32 <51> was carried out. Sample vials comprising F4H5 or F6H8,respectively, were inoculated with Escherichia coli, Pseudomonasaeruginosa, Staphylococcus aureus, Candida albicans and Aspergillusniger and incubated at approx. 22.5° C. The results are given in tables6 and 7.

In result, no increase but a substantial decrease in the concentrationof colony-forming units (cfu) over 24 and 48 hours was observed.Obviously, the compounds do not support microbial growth, but ratherinhibit it in the same manner as if an effective amount of anantimicrobial preservative had been added.

TABLE 6 F6H8 (pure) cfu/mL Change in log steps Organism 0 h 24 h 48 h 6d 24 h 48 h 6 d E. coli (ATCC 8739) 1 600 <100 <100 n.d. ≤−1.2 ≤−1.2n.d. P. aeruginosa (ATCC 9027) 1 600 <100 <100 n.d. ≤−1.2 ≤−1.2 n.d. S.aureus (ATCC 6538) 2 900 <100 <100 n.d. ≤−1.4 ≤−1.4 n.d. C. albicans(ATCC 10231) 1 500 <100 <100 n.d. ≤−1.2 ≤−1.1 n.d. A. niger (ATCC 16404)1 500 <100 <100 <100 ≤−1.2 ≤−1.2 ≤−1.2

TABLE 7 F4H5 (pure) cfu/mL Change in log steps Organism 0 h 24 h 48 h 6d 24 h 48 h 6 d E. coli (ATCC 8739) 1 600 <100 <100 n.d. ≤−1.2 ≤−1.2n.d. P. aeruginosa (ATCC 9027) 1 600 <100 <100 n.d. ≤−1.2 ≤−1.2 n.d. S.aureus (ATCC 6538) 2 900 <100 <100 n.d. ≤−1.4 ≤−1.4 n.d. C. albicans(ATCC 10231) 1 500 <100 <100 n.d. ≤−1.2 ≤−1.1 n.d. A. niger (ATCC 16404)3 000 <100 <100 <100 ≤−1.4 ≤−1.2 ≤−1.2

The invention claimed is:
 1. A pharmaceutical composition comprising:(a) a therapeutically effective amount of a poorly water-solubleprostaglandin analogue selected from the group consisting oflatanoprost, bimatoprost, tafluprost, travoprost and unoprostone, and(b) a liquid vehicle comprising a semifluorinated alkane selected fromF4H5, F4H6, F6H6 and F6H8; wherein the composition is substantially freeof water and free of a preservative, and wherein the composition isformulated as a solution, emulsion or suspension.
 2. The composition ofclaim 1, wherein the active ingredient is latanoprost.
 3. Thecomposition of claim 2, wherein the concentration of latanoprost is fromabout 0.001 wt.-% to about 0.01 wt.-%.
 4. The composition of claim 1,wherein the composition is formulated as a solution.
 5. The compositionof claim 1, further comprising an organic co-solvent.
 6. The compositionof claim 5, comprising ethanol at a concentration of about 1.5 wt.-% orless, or of about 1.0 wt.-% or less.
 7. The composition of claim 1,wherein the semifluorinated alkane is F4H5.
 8. The composition of claim7, wherein the composition is formulated as a solution.
 9. Thecomposition of claim 8, further comprising an organic co-solvent. 10.The composition of claim 9, wherein the organic co-solvent is ethanol ata concentration of about 1.5 wt.-% or less.
 11. The composition of claim7, wherein the active ingredient is latanoprost.
 12. The composition ofclaim 11, wherein the concentration of latanoprost is from about 0.001wt.-% to about 0.01 wt.-%.
 13. The composition of claim 12, wherein thecomposition is formulated as a solution.
 14. The composition of claim13, further comprising an organic co-solvent.
 15. The composition ofclaim 14, wherein the organic co-solvent is ethanol at a concentrationof about 1.5 wt.-% or less.
 16. A pharmaceutical kit comprising thecomposition of claim 1 and a container holding the composition, whereinthe container has a dispensing means.
 17. A pharmaceutical kitcomprising the composition of claim 11 and a container holding thecomposition, wherein the container has a dispensing means.